Efficacy of Oral SERDs in the treatment of ER+, HER2 - metastatic breast cancer, a stratified analysis of the ESR1 wild type and mutant subgroups.

BACKGROUND: Oral SERDs are a novel drug class that have been developed to counteract resistance due to ESR1 mutations. Several SERDs have emerged from phase 2 and 3 trials, with the FDA limiting approval for Elacestrant to patients with ESR1mt tumours despite PFS benefit in the overall population. However, questions remain on whether patients with ESR1wt tumours stand to benefit from oral SERDs. PATIENTS AND METHODS: Manuscripts and conference presentations of Randomised Controlled Trials were extracted after a systematic search of Embase, PubMed and Cochrane from inception until January 21,2023. RCTs investigating the efficacy of oral SERDs versus endocrine therapy for ER positive, HER2 negative advanced breast cancer, and which reported the Kaplan Meier (KM) curves of PFS in the overall and ESR1 mutant (ESR1mt) population were selected. A graphical reconstructive algorithm was applied to estimate time-to-event outcomes from reported KM curves in all overall and ESR1mt cohorts. A bipartite matching algorithm, KMSubtraction, was used to derive survival data for unreported (ESR1wt) subgroups. An individual patient data (IPD) meta-analysis was then pursued, pooling data by ESR1 mutation status in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane Guidelines for IPD. RESULTS: The randomized clinical trials ACELERA, AMEERA-3, EMERALD and SERENA-2 were included, totalling 1290 patients. In the pooled analysis of the overall cohort, PFS benefit was observed with oral SERDs when compared with treatment of physicians choice (TPC) (HR 0.783, 95%CI 0.681-0.900, p<0.001). In the ESR1mt subgroup, oral SERDs demonstrated improved PFS (HR 0.557, 95%CI 0.440-0.705, p<0.001) compared to TPC. In the ESR1wt subgroup, oral SERDs demonstrated no significant PFS benefit (HR 0.944, 95%CI 0.783-1.138, p=0.543) when compared to TPC. CONCLUSIONS: The results of this IPD meta-analysis suggests that PFS benefit in the overall population is mainly driven by the ESR1mt subgroup.

Culturally adapted psychosocial interventions (CaPSI) for early psychosis in a low-resource setting: study protocol for a large multi-center RCT.

BACKGROUND: Psychosis treatment guidelines recommend cognitive behaviour therapy (CBT) and family intervention (FI), for all patients with first episode psychosis (FEP), though guidance borrows heavily from literature in adults from high income countries. To our knowledge, there are few randomized controlled trials (RCTs) examining the comparative effect of these commonly endorsed psychosocial interventions in individuals with early psychosis from high-income countries and no such trials from low and middle-income countries (LMICs). The present study aims to confirm the clinical-efficacy and cost-effectiveness of delivering culturally adapted CBT (CaCBT) and culturally adapted FI (CulFI) to individuals with FEP in Pakistan. METHOD: A multi-centre, three-arm RCT of CaCBT, CulFI, and treatment as usual (TAU) for individuals with FEP (n = 390), recruited from major centres across Pakistan. Reducing overall symptoms of FEP will be the primary outcome. Additional aims will include improving patient and carer outcomes and estimating the economic impact of delivering culturally appropriate psychosocial interventions in low-resource settings. This trial will assess the clinical-efficacy and cost-effectiveness of CaCBT and CulFI compared with TAU in improving patient (positive and negative symptoms of psychosis, general psychopathology, depressive symptoms, quality of life, cognition, general functioning, and insight) and carer related outcomes (carer experience, wellbeing, illness attitudes and symptoms of depression and anxiety). CONCLUSIONS: A successful trial may inform the rapid scale up of these interventions not only in Pakistan but other low-resource settings, to improve clinical outcomes, social and occupational functioning, and quality of life in South Asian and other minority groups with FEP. TRIAL REGISTRATION: NCT05814913.

Evaluating paediatric dermatology telephone clinics during COVID-19 from a dual clinician and patient perspective: a prospective study.

BACKGROUND: The landscape of dermatology services, already rapidly evolving into an increasingly digital one, has been irretrievably altered by the COVID-19 (SARS-CoV-2) pandemic. Data are needed to assess how best to deliver virtual dermatology services in specific patient subgroups in an era of ongoing social distancing and beyond. Initial studies of teledermatology in paediatric populations suggest that many of the problems experienced in adult telemedicine are more apparent when treating children and come with additional challenges. AIM: To evaluate the efficacy of a virtual paediatric dermatology telephone clinic in comparison to traditional face-to-face (FTF) clinics, both from the clinician and patient/parental perspective. METHODS: We carried out a prospective service evaluation examining a single centre cohort of paediatric dermatology patients managed during the COVID-19 pandemic via a telephone clinic supported by images. The study period covered June-September 2020. Data on outcomes were collected from clinicians and a qualitative patient/parental telephone survey was undertaken separately. A five-point Likert scale was used to assess both satisfaction and levels of agreement regarding whether a telephone clinic was more convenient than an FTF clinic. RESULTS: Of 116 patients included, 24% were new and 76% were follow-up patients, with a mixture of inflammatory dermatoses (75%) and lesions (25%). From the clinician's perspective, most consultations (91%) were successfully completed over the telephone. However, qualitative patient and parent feedback paradoxically illustrated that although nearly all (98%) respondents had no outstanding concerns, 52% felt highly unsatisfied and only 22% agreed that telephone clinics were more convenient. Most (65%) preferred FTF follow-up in the future. Statistical analysis using χ² test showed that among those with established follow-ups, the preference for future consultation type was independent of specific reasons for follow-up. CONCLUSIONS: Our study demonstrates a clear discrepancy between the practical successes of a virtual service from the clinician's perspective compared with the patient/parental perspective. Parental anxiety appears to be less effectively allayed virtually than with FTF. This raises the question of whether there is a role for virtual paediatric telephone clinics in the postpandemic future, which may be better left to patients/parents to decide on an individual basis.

Survival of women with inflammatory breast cancer: a large population-based study.

BACKGROUND: Our group has previously reported that women with inflammatory breast cancer (IBC) continue to have worse outcome compared with those with non-IBC. We undertook this population-based study to see if there have been improvements in survival among women with stage III IBC, over time. PATIENT AND METHODS: We searched the Surveillance, Epidemiology and End Results Registry to identify female patients diagnosed with stage III IBC between 1990 and 2010. Patients were divided into four groups according to year of diagnosis: 1990-1995, 1996-2000, 2001-2005, and 2006-2010. Breast cancer-specific survival (BCSS) was estimated using the Kaplan-Meier method and compared across groups using the log-rank test. Cox models were then fit to determine the association of year of diagnosis and BCSS after adjusting for patient and tumor characteristics. RESULTS: A total of 7679 patients with IBC were identified of whom 1084 patients (14.1%) were diagnosed between 1990 and 1995, 1614 patients (21.0%) between 1996 and 2000, 2683 patients (34.9%) between 2001 and 2005, and 2298 patients (29.9%) between 2006 and 2010. The 2-year BCSS for the whole cohort was 71%. Two-year BCSS were 62%, 67%, 72%, and 76% for patients diagnosed between 1990-1995, 1996-2000, 2001-2005, and 2006-2010, respectively (P < 0.0001). In the multivariable analysis, increasing year of diagnosis (modeled as a continuous variable) was associated with decreasing risks of death from breast cancer (HR = 0.98, 95% confidence interval 0.97-0.99, P < 0.0001). CONCLUSION: There has been a significant improvement in survival of patients diagnosed with IBC over a two-decade time span in this large population-based study. This suggests that therapeutic strategies researched and evolved in the context of non-IBC have also had a positive impact in women with IBC.

New CYP17 hydroxylase inhibitors: synthesis, biological evaluation, QSAR, and molecular docking study of new pregnenolone analogs.

A new series of pregnenonlone analogs were synthesized and evaluated for their inhibitory activity against cytochrome P450 (CYP17 hydroxylase enzyme). In general, the 5-aryl-1,3,4-thiadiazol-2-yl)-imino-pregnenolone derivatives 11-15 were more active than the sulfonate 24-31 and the ester 37-41 analogs. Derivative 12 showed optimal activity in this series, with IC50 values of 2.5 µM compared with the standard abiraterone (IC50 = 0.07 µM). However, the analogs 11 and 25 showed a better selectivity profile (81.5 and 82.7% inhibition of hydroxylase, respectively), which may be a useful lead in CYP17 inhibition studies. Molecular docking studies demonstrated quite similar binding patterns of all new pregnenolone derivatives at the active site of CYP17 through hydrogen bonding and hydrophobic interaction.

Synthesis and Characterization of a Novel Quaternary Ammonium Salt as a Corrosion Inhibitor for Oil-Well Acidizing Processes.

A quaternary ammonium salt, 1,1'-(1,4-phenylenebis(methylene))bis(4-formylpyridin-1-ium) (PMBF), was synthesized, characterized, and investigated as an inhibitor for C1018 (type steel in oil wells) corrosion in 17.5% HCl solution. The chemical structure of PMBF was confirmed using altered techniques. Potentiodynamic polarization (PDP) was employed to investigate the corrosion inhibition effect of the synthesized compound in a 17.5% HCl solution for C1018. The corrosion protection was increased by improving the dose of the synthesized compound and reached 98.5% at 42.02 × 10-5 M and 313 K. On the other hand, it was decreased by increasing the temperature and reached 97.9% at the same concentration and 343 K. The parameters of activation and adsorption were calculated and debated. A polarization study revealed that PMBF functioned as a "mixed-kind inhibitor," i.e., affecting both cathodic and anodic processes through their adsorption onto the electrode surface. The adsorption was described by the Langmuir adsorption isotherm. Different techniques were employed as appropriate tools for analyzing the structure of the layer formed on C1018. Density functional theory (DFT) and Monte Carlo (MC) simulations were used to compare the results of the theoretical calculations with the experiments. Finally, an appropriate inhibition mechanism was suggested and discussed.

Identifying factors that impact survival among women with inflammatory breast cancer.

BACKGROUND: The objective of this retrospective study was to determine factors impacting survival among women with inflammatory breast cancer (IBC). METHODS: The Surveillance, Epidemiology and End Results Registry (SEER) was searched to identify women with stage III/IV IBC diagnosed between 2004 and 2007. IBC was identified within SEER as T4d disease as defined by the sixth edition of the American Joint Committee on Cancer. The Kaplan-Meier product-limit method was used to describe inflammatory breast cancer-specific survival (IBCS). Cox models were fitted to assess the multivariable relationship of various patient and tumor characteristics and IBCS. RESULTS: Two thousand three hundred and eighty-four women with stage IIIB/C and IV IBC were identified. Two-year IBCS among women with stage IIIB, IIIC and IV disease was 81%, 67% and 42%, respectively (P < 0.0001). In the multivariable model, patients with stage IIIB disease and those with stage IIIC disease had a 63% [hazard ratio (HR) 0.373, 95% confidence interval (CI) 0.296-0.470, P < 0.001] and 31% (HR 0.691, 95% CI 0.512-0.933, P = 0.016) decreased risk of death from IBC, respectively, compared with women with stage IV disease. Other factors significantly associated with decreased risk of death from IBC included low-grade tumors, being of white/other race, undergoing surgery, receiving radiation therapy and hormone receptor-positive disease. Among women with stage IV disease, those who underwent surgery of their primary had a 51% decreased risk of death compared with those who did not undergo surgery (HR = 0.489, 95% CI 0.339-0.704, P < 0.0001). CONCLUSIONS: Although IBC is an aggressive subtype of locally advanced breast cancer, it is heterogeneous with various factors affecting survival. Furthermore, our results indicate that a subgroup of women with stage IV IBC may benefit from aggressive combined modality management.

Adverse events risk associated with bevacizumab addition to breast cancer chemotherapy: a meta-analysis.

BACKGROUND: Bevacizumab is a monoclonal antibody against vascular endothelial growth factor with the ability to increase progression-free survival in metastatic breast cancer (MBC). A systematic review and meta-analysis was conducted to determine the risk of the most clinically relevant adverse outcomes associated with the use of bevacizumab in the treatment of breast cancer. PATIENTS AND METHODS: We included phase III clinical trials that used bevacizumab alone or in combination with chemotherapy as for MBC or locally recurrent. Statistical analyses were conducted to calculate summary odds ratio (OR) of the eight most relevant adverse outcomes related with bevacizumab. RESULTS: Five clinical trials were included in the meta-analysis. Summary odds ratios obtained showed a statistically significant bevacizumab-associated increased risk in four of the adverse outcomes studied: proteinuria (OR = 27.68), hypertension (OR = 12.76), left ventricular dysfunction (LVD) (OR = 2.25), and hemorrhagic events (OR = 4.07). No statistically significant differences were found for gastrointestinal (GI) perforation, vascular events, fatal events, or febrile neutropenia. CONCLUSIONS: Bevacizumab did increase the risk of LVD and hemorrhagic events. The addition of bevacizumab to chemotherapy in patients with metastatic breast cancer was not associated with a significant increase in grade ≥ 3 arterial or venous thromboembolic events, GI perforation, or fatal events.

WHO/INRUD patient care and facility-specific drug use indicators at primary health care centres in Eastern province, Saudi Arabia.

This study aimed to measure the performance of primary health care centres in Eastern province, Saudi Arabia, using the WHO/International Network of Rational Use of Drugs patient care and facility-specific drug use indicators. In a cross-sectional study, 10 health centres were selected using systematic random sampling. A total of 300 patients were interviewed while visiting the centre from January to March 2011 and 10 pharmacists from the same centres were interviewed. Average consultation time was 7.3 min (optimal > or = 30 min), percentage of drugs adequately labelled was 10% (optimal 100%) and patient's knowledge of correct dosage was 79.3% (optimal 100%). The percentage of key drugs in stock was only 59.2% (optimal 100%). An overall index of rational facility-specific drug use was calculated and applied to rank the health centres for benchmarking.

Evaluation of IgM and IgG in COVID-19 Recovered Patients in Iraq.

Severe acute respiratory syndrome coronavirus-2 is a major threat to health care worldwide with high morbidity and mortality. Therefore, understanding the role of immune mechanisms and humoral response is vital in this disease. The present study aimed to investigate the relationship between Immunoglobulins (IgM, IgG) in COVID-19 recovered patients with age, gender, and severity of the disease. The duration of effect of antibody levels and protection against re-infection has also been evaluated in the patients. Three groups participated in this study; group 1: 0-14 days after recovery, group 2: 2 months after recovery, group 3: 3 months after recovery, group 4: 4-6 months after recovery, group 5: more than 6 months. The nasopharyngeal swab was used to confirm recovery by Real-Time Polymerase Chain Reaction (RT-PCR) technique. IgM and IgG antibody levels were evaluated using Enzyme-Linked Immuno Fluorescent Assay (ELIFA) technique. The results indicated that the IgM levels increased for one month during the seven days after infection and then decreased in most patients (P≤0.05). The mean of IgG in group 1 increased compared to those of other studied groups. A significant decrease was observed in group 2 compared to group 1, as well as in group 3 compared to groups 1, and 2. Also, a significant difference existed between group 4 compared to groups 1, 2, and 3. Finally, significant differences were noticed between group 5 compared to groups 1, 2, 3, and 4 (P≤0.05). No significant differences were observed in antibodies level between male, and female COVID-19 recovered patients in groups 1, 2, 3, 4, and 5 (P≤0.05). Finally, highly significant differences in IgG levels between mild, moderate, and severe subgroups in groups 1 and 2. The present study demonstrated that IgM and IgG against SARS-CoV-2 appeared in the early stages of the disease and decreased after 1 month and failed to maintain high levels during the 6-month observation.

International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment.

BACKGROUND: Inflammatory breast cancer (IBC) represents the most aggressive presentation of breast cancer. Women diagnosed with IBC typically have a poorer prognosis compared with those diagnosed with non-IBC tumors. Recommendations and guidelines published to date on the diagnosis, management, and follow-up of women with breast cancer have focused primarily on non-IBC tumors. Establishing a minimum standard for clinical diagnosis and treatment of IBC is needed. METHODS: Recognizing IBC to be a distinct entity, a group of international experts met in December 2008 at the First International Conference on Inflammatory Breast Cancer to develop guidelines for the management of IBC. RESULTS: The panel of leading IBC experts formed a consensus on the minimum requirements to accurately diagnose IBC, supported by pathological confirmation. In addition, the panel emphasized a multimodality approach of systemic chemotherapy, surgery, and radiation therapy. CONCLUSIONS: The goal of these guidelines, based on an expert consensus after careful review of published data, is to help the clinical diagnosis of this rare disease and to standardize management of IBC among treating physicians in both the academic and community settings.

Mechanisms and management of doxorubicin cardiotoxicity.

Doxorubicin is an effective anti-tumor agent with a cumulative dose-dependent cardiotoxicity. In addition to its principal toxic mechanisms involving iron and redox reactions, recent studies have described new mechanisms of doxorubicin-induced cell death, including abnormal protein processing, hyper-activated innate immune responses, inhibition of neuregulin-1 (NRG1)/ErbB(HER) signalling, impaired progenitor cell renewal/cardiac repair, and decreased vasculogenesis. Although multiple mechanisms involved in doxorubicin cardiotoxicity have been studied, there is presently no clinically proven treatment established for doxorubicin cardiomyopathy. Iron chelator dexrazoxane, angiotensin converting enzyme (ACE) inhibitors, and ß-blockade have been proposed as potential preventive strategies for doxorubicin cardiotoxicity. Novel approaches such as anti-miR-146 or recombinant NRG1 to increase cardiomyocyte resistance to toxicity may be of interest in the future.

Outcome of low birth weight infants in Diyala province of Iraq.

OBJECTIVES: To measure birth weight-specific mortality rates in the Diyala Province of Iraq and to determine if the causes of neonatal death could identify interventions needed to reduce neonatal mortality rates. METHOD: We retrospectively compared the outcome of 196 neonates with birth weight 500-2499 g admitted in 2003 with 252 such neonates admitted in 2009. RESULTS: The mortality rate in very low birth weight infant (VLBWI) increased from 12/80 (15%) in 2003 to 51/152 (33.6%) in 2009, (p = 0.003). In LBWI, 10/116 (8.6%) died in 2003 compared to 33/152 (13%) in 2009 (p = 0.29). Sepsis accounted for 35.2% of deaths in VLBWI and 39% in LBWI, Perinatal depression explained 39.2% of deaths in VLBWI and 24.2% in LBWI. CONCLUSION: The VLBWI mortality in the Diyala province of Iraq doubled in the last 6 years reaching 33.6% in 2009, LBWI mortality increased by 50% reaching 13%. Sepsis and perinatal depression accounted for at least two-third of the deaths.

The attitude and awareness of contact lens use among medical students of King Faisal University, Al Ahsa, Saudi Arabia.

BACKGROUND: Not many studies have investigated the knowledge outcomes among medical students with regards to contact lenses (CL). Thus, in this study, we aim to assess the attitude and awareness of CL use and the associated factors among medical students of King Faisal University (KFU), Al Ahsa, Saudi Arabia. METHODS: This a cross-sectional study that based developed based on a designed questionnaire that was composed of 31 questions with a maximum score of 57 points. We have also conducted a linear regression model to explore the possible important factors that may affect the level of knowledge and awareness about contact lenses care. RESULTS: A total of 208 participants were included in this study, with a mean age of 21.0 ± 1.9, and 56.3% (n = 117) of them being females. The total mean knowledge score in our study was 30.1 ± 7.74, which was higher in females (31.5 ± 7.09) than in male participants (28.7 ± 7.69). The results of the linear regression model showed that being female (E = -0.37; 95%CI = -0.65- -0.10; P = 0.007), using contact lenses (E = 0.56; 95%CI = 0.29 - 0.82; P < 0.001), and in the third year (E = 0.66; 95%CI = 0.19- 1.13; P = 0.007) is significantly correlated with having higher knowledge scores about using CLs. CONCLUSION: Female participants had higher total mean knowledge scores than males. We recommend that further educational campaigns should be inaugurated to raise awareness about taking care of CLs and enhancing the related practices of wearing them.

Survival differences among women with de novo stage IV and relapsed breast cancer.

BACKGROUND: The objective of this retrospective study was to determine whether differences in survival exist between women with de novo stage IV and relapsed breast cancer. PATIENTS AND METHODS: Three thousand five hundred and twenty-four women with de novo stage IV or relapsed breast cancer diagnosed from 1992 to 2007 were identified. Disease-free interval (DFI) was defined as the time from the diagnosis of primary nonmetastatic breast cancer to the date of the first distant metastases. Kaplan-Meier product limit method was used to estimate overall survival (OS). Cox proportional hazards model was fitted to determine the association between metastatic disease (relapsed versus de novo) and OS after controlling for other patient/tumor characteristics. RESULTS: Six hundred and forty-three (18.2%) women had de novo stage IV disease and 2881 (81.8%) had relapsed disease. Median follow-up was 19 months. Median OS among patients with de novo stage IV and relapsed disease was 39.2 and 27.2 months, respectively (P < 0.0001). In the multivariable model, women with relapsed disease had an increased risk of death compared with patients with de novo disease (HR = 1.75, 95% confidence interval 1.47-2.08, P < 0.0001). When the multivariable model was stratified by DFI, women with relapsed disease with DFI <6 months, ≥6 months to <2 years, or ≥2 to <5 years each had a significantly higher risk of death compared with women with de novo stage IV disease. The risk of death was not statistically different among patients with relapsed disease with DFI >5 years compared with those with de novo disease. CONCLUSIONS: This large cohort study provides further insight into the natural history of relapsed and de novo stage IV breast cancer. DFI plays an important role in the prognosis for patients with relapsed breast cancer.

Incidence of and survival following brain metastases among women with inflammatory breast cancer.

BACKGROUND: The purpose of this study was to determine the incidence of and survival following brain metastases among women with inflammatory breast cancer (IBC). PATIENTS AND METHODS: Two hundred and three women with newly diagnosed stage III/IV IBC diagnosed from 2003 to 2008, with known Human epidermal growth factor receptor 2 (HER2) and hormone receptor status, were identified. Cumulative incidence of brain metastases was computed. Survival estimates were computed using the Kaplan-Meier product limit method. Multivariable Cox proportional hazards models were fitted to explore the relationship between breast tumor subtype and time to brain metastases. RESULTS: Median follow-up was 20 months. Thirty-two (15.8%) patients developed brain metastases with a cumulative incidence at 1 and 2 years of 2.7% and 18.7%, respectively. Eleven (5.3%) patients developed brain metastases as the first site of recurrence with cumulative incidence at 1 and 2 years of 1.6% and 5.7%, respectively. Compared with women with triple receptor-negative IBC, those with hormone receptor-positive/HER2-negative disease [hazard ratio (HR) = 0.55, 95% confidence interval (CI) 0.19-1.51, P = 0.24] had a decreased risk of developing brain metastases, and those with HER2-positive disease (HR = 1.02, 95% CI 0.43-2.40, P = 0.97) had an increased risk of developing brain metastases, although these associations were not statistically significant. Median survival following a diagnosis of brain metastases was 6 months. CONCLUSION: Women with newly diagnosed IBC have a high early incidence of brain metastases associated with poor survival and may be an ideal cohort to target for site-specific screening.